3-hydroxy-4, 4-diphenyl-6-aminoheptanes



Patented Aug. 28, 1951 UNITED STATES PATENT OFFICE 3-HYDROXY-4A-DIPHENYL-6- AMINOHEPTANES Robert L. Clark, Woodbridge, N. J., assignor to Merck & Co., Inc., Rahway, N. J a corporation of New Jersey Claims.

This invention relates to the preparation of new compounds characterized by analgesic properties. More particularly, it relates to compounds such as 3-hydroxy-4,4-diphenyl-6-diakylaminoalkanes, S-hydroxy 4,4 diphenyl-6- morpholinoalkanes. acylated 3-hydroxy-4,4-diphenyl-6-dialkylaminoalkanes, acylated 3 hydroxy-4,4-diphenyl-6-morpholinoalkanes and the like, their salts and to methods for their preparation. These new products useful as analgesics, and as substitutes for morphine, can be represented by the following general formula:

wherein R1 is a phenyl group, R2 is a radical selected from the group consisting of aliphatic amino, aromatic amino and heterocyclic amino, R3 is selected from the group consisting of hydrogenand alkyl, R4 is a radical selected from the group consisting of OH and O-acyl.

This application is a division of application Serial No. 11,831, filed February 27, 1948.

It is well known that compounds such as 4.4- diphenyl-G-dimethylamino-3-heptanone (amidone) are potent analgesics. Amidone was developed in Germany and is described in the Department of Commerce (office of the Publication Board) Report OPB 981 dated July 1945.

I have now found that 3-hydroxy-4,4-diphenyl- G-dialkylaminoalkanes and acylated 3-hydroxy- 4,4 diphenyl 6 dialkylaminoalkanes possess analgesic properties superior to amidone. For example, 3 hydroxy-4,4-diphenyl-6-dimethylaminoheptane has its maximum analgesic effect three hours after injection, whereas in the case of amidone the eifect usually begins to wear oil after one hour. Also, the compound 3-acetoxy-4,4-diphenyl-6-dimethyltminoheptane is a more potent analgesic than the corresponding 3-ketone. Thus the 3-hydroxy 4,4 diphenyl-6-dialkylaminoalkanes and the acylated 3-hydroxy-4,4-diphenyl-6-dialkylaminoalkanes constitute new and important analgesics which can be used as substitutes of morphine, These compounds excel amidone in many respects in that they are less toxic and display more potent analgesic properties.

In the preparation of these compounds in accordance with my invention herein disclosed, ketones such as 4,4-diphenyl-6-dimethylamino- 3-heptanone, 4,4-diphenyl-6-morpholino-3-hexanone or the like are first subjected to hydrogenation. The hydrogenation may be carried out at room temperature in the presence of a suit- 2 able catalyst such as platinum oxide at a' pressure of approximately 40 lbs. of hydrogen. Alternatively, the hydrogenation can be accomplished in about 30 minutes, with the use of high temperatures and pressures preferably in the presence of Raney nickel. An ether solution of lithium aluminum hydride also produces the hydrogenation. The keto group is thereby reduced to form a secondary alcohol group in the 3 position.

My invention concerns the preparation of these substituted alcohols which possess analgesic properties and are important intermediates in the preparation of acylated compounds which also possess analgesic properties.

The acylated compounds of my invention may be prepared by refluxing secondary alcohols such as 3-hydroxy 4,4 diphenyl-6-dimethylaminoheptane, 3 hydroxy-4,4-diphenyl-6-morpholino hexane or the like, preferablyin the form of their hydrohalide salts, with an acylating agent. Suitable acylating agents are for example acetic anhydride, propionyl chloride, 4-nitrobenzoy1 chloride, formic-acetic anhydride, and the like. It is usually preferred to use a large excess of the acylating agent. When using 4-nitrobenzoyl chloride as the acylating agent the 3(4'-nitrobenzoxy)-4,4-diphenyl compound is formed. This compound may be further reduced to form the 3(4'-aminobenzoxy) derivative, which compound may in turn be acylated to form a 3(4'- acylaminobenzoxy) 4'4-diphenyl alkane.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

. ylamino-3-heptanone hydrochloride in 100 ml. of

water was hydrogenated at 40 lbs. pressure of hydrogen at room temperature in the presence of 0.2 'g. of platinum oxide. A small excess of hydrogen was absorbed. The catalyst was removed by filtration and the solvent removed in vacuo leaving 3 g. of 3-hydroxy-4,4-diphenyl-6-dimethylaminoheptane hydrochloride which was crystallized from methanol-ether; M. P. 191l92;

Anal. calcd. for C21H29ONCLHC1; C, 72.49; H, 8.69; N, 4.03. Found: C, 72.23; H, 8.53; N, 3.96.

EXAMPLE 2 3Jig (boxy-4,4-diphenyl-6-dimethylaminoheptane A solution of 6.2 g. of 4,4-diphenyl-6-dimethylamino-B-heptanone in 140 ml. of methanol was heated to 185 for 30 minutes at 2000 lbs. pressure of hydrogen in the presence of 3 g. of Raney nickel. The nickel was removed and the solvems distilled in vacuo. The remaining oil (6 g.) was dissolved in 150 ml. of ether and an excess of dry hydrogen chloride was passed into the solution. The hydrochloride of 3-hydroxy-4,4-diphenyl-G-dimethylaminoheptane could be crystallized from ethanol-ether.

EXAIVIPLE 3 3-hydro.ry-4,4-diphenyl-6gdimethylaminoheptane In a flask equipped with an addition funnel, a condenser and a stirrer was placed a solution of1.3 g. of lithium aluminum hydride in 50 ml. of ether. An ether solution of 9 g. of 4,4-diphenyl-6-dimethylamino-3-heptanone in 50 ml. of ether was added slowly. After fifteen minutes ml. of water was added cautiously followed by 30 ml. of 2.5 N hydrochloric acid and ml. of concentrated hydrochloric acid. Two clear liquid phases were present. After one hour the product had crystallized from the aqueous phase. This was removed by filtration and dissolved in 20 ml. of hot water. Upon cooling, filtering, and drying, 8.8 g. of white solid was obtained. This was crystallized from ml. of ethanol by the addition of 200 ml. of ether to yield 8 g. of 3-hydroxy-4,4-diphenyl-.6-dimethylaminoheptane hydrochloride, M. P. 189190 C.

8.27; N, 3.59. Found: C. 70.55; H, 8.18; N, 3.59.

EXAMPLE 5 3-propionoa:y-4,4-diphenyl-fi-dimethylaminoheptane (5H5 cnacm-cn-ocnzcncm cocnzom 2 g. of the 3-hydroxy-heptane hydrochloride obtained in accordance with Example 1, 2 or 3 was heated to refluxing with 8 times is weight of propionyl chloride (15 ml.) for 1 hour. The solvents were removed and 2 g. of an oil (3-propionoxy-4,4-diphenyl 6 dimethylaminoheptane HCl) was obtained, which crystallized from ethanol-ether; M. P. 185.

Anal. calcd. for C24H33NO2.HC11 C, 71.35; H, 8.48; N, 3.47. Found: C, 70.79; H, 7.91; N, 3.71.

EXAMPLE 6 3-formo:z:y-4,4-diphenyl-G-dimethylaminoheptane Three grams of the 3-hydroxy heptane hydrochloride obtained in accordance with Example 1. 2 or 3 was heated to reflux temperature with 11 g. of formic-acetic anhydride for one hour. The solvents were removed leaving 3 g. of an oil. This was triturated with ether to yield 2 g. of a solid which was crystallized from alcoholether and water to give 1.0 g. of 3-f0rmoxy-4,4- diphenyl-6-dimethylaminoheptane hydrochloride dihydrate, M. P. 115-120.

Anal. calcd. for. Cz2I-I29NOz.2I-I2O.HCl: C, 64.14; H, 8.32; N, 3.40. Found: C, 64.78; H, 8.31; N.

EXAMPLE 7 3-hydrozy-4,4-diphenyl-6-morpholinoheptane C5115 CHa-CHzCH( JCHzCH-Cl1s H 5H5 N H1 0 CH;

Hz Hz A solution of 2.16 g. of 4,4-diphenyl-6-morpholino-3-heptanone hydrobromide in ml. of methanol was hydrogenated at 40 lbs. pressure of hydrogen at room temperature in the presence of 100 mg. of platinum oxide. After the catalyst was removed by filtration, the solvents were distilled in vacuo and the residue, 2 g. of 3-hydroxy- 4,4-diphenyl 6 morpholino-heptane hydrobromide crystallized from ethanol-ether; M. P. 221.

Anal. calcd. for CzzHazNOzBr: C, 63.59; 11,7.43; N, 3.23. Found: C, 64.59; H, 7.17; N, 3.29.

EXAMPLE 8 3-acetoxy-4,4-diphenyl-6-morpholinoheptane CaHs cH.oH1cH-J:cH:oH-cm 5H5 II\T c 0 on, H, 0

EXAMPLE 9 3-propiono:cy-4,4-diphenyl-6-morpholinoheptane CIHs CHa-CHa-CHC-CHr-CHCH5 CtHa N 1.5 g. of 3-hydroxy-4,4-dipheny1-6 morpholinoheptane hydrobromide was heated heated to reflux temperature with 10-times its weight of propionyl chloride for one and one-half hours. The solvents were removed and the residue (1.2 g.) of 3proplonoxy-4,4-diphenyl-6-morpholinoheptane hydrobromide crystallized from ethanol: M. P. 120-5 (previous softening).

Anal. calcd. for CzaI-IasNOaHBr: C, 63.67; H, 7.40; N, 2.86. Found: C, 64.19; H, 7.59; N, 2.77.

EXAMPLE 10 3-acetomy-4,4-diphenyZ-6-morpholinohea:ane

CuHs

CHaCH:CH-C--CHz-CH2 COCH3 Hag (1H1 H2 CH1 3.6 g. of 4,4-diphenyl-6-morpholino-3-hexanone was dissolved in 75 ml. of methanol and heated to 185 and 2000 lbs. pressure of hydrogen in the presence of 2 g. of Raney nickel. The catalyst was removed by filtration and the solvents removed in vacuo. The product (3.5 g.) of 3 hydroxy-4,4-diphenyl-6-morpholinohexane was a viscous gum as wellas its hydrochloride.

3.5 g. of 3-hydroxy-4,4-diphenyl-6-morpholinohexane hydrochloride was heated with 10 times its weight of acetic anhydride for 1 hour. The solvents were removed and the residue (1.5 g.) of 3 acetoxy-4,4-diphenyl-6-morpholinohexane hydrochloride crystallized from methanol-ether; M. P. 242-243.

Anal. calcd. for C24Ha1NOaHCl: C, 68.96; H,

7.72; N, 3.35. Found: C, 69.04; H, 7.66; N, 3.54.

EXAMPLE 11 3(4'-nitrobenzoxy) -4,4-diphenyZ-6-dimethylaminoheptane To a mixture of 1.8 g. of 3-hydroxy-4,4-diphenyl-6-dimethylaminoheptane hydrochloride, 50 ml. of water, 1.6 g. of sodium bicarbonate and 50 ml. of ether was added a solution of 1.85 g. of 4-nitrobenzoyl chloride in 50 ml. of ether. The mixture was stirred mechanically for 1% hours and then allowed to stand 18 hours. The solid at the interface was removed by filtration and shown to be 4-nitrobenzoic anhydride. The ether layer was dried and dry hydrogen chloride passed into it until there was no further precipitation of a gum. This gum, weighing 1.8 g., was dissolved in 25 ml. methanol. 10 ml. of benzene added and the solution evaporated to dryness. This residue was dissolved in 25 m1. of methanol and upon the addition of 100 ml. of ether 1.5 g. of crystals of 3(4 '-nitrobenzoxy) -4,4-diphenyl fi-dimethyl-aminoheptane hydrochloride separated (M. P. 223-224).

Anal. calcd. for CzsI-Is2NzO4.HCl: C, 67.66; H, 6.69; N, 5.64. Found: C, 67.39; H, 7.06; N, 5.57.

EXAMPLE '12 3(4' aminobenzomu) l 4,4-diphenyl-6-dimethyl v aminoheptane Coat CH|CH:CH Aim-on on:

NHt/

6.5 g. of 3(4'-nltrobenzoxy) -4,4-diphenyl-6-dimethylaminoheptane hydrochloride was suspended in 50 ml. of water, an excess of sodium hydroxide was added and the free base was extracted into ether. The ether was removed in vacuo and the 6 g. residue was dissolved in ml. of methanol and hydrogenated at 40 lbs. pressure of hydrogen in the presence of 5 g. of Raney nickel. The catalyst was removed by filtration. The residue (5.5 g.) was dissolved in 200 ml. of ether and excess dry hydrogen chloride was passed into the solution precipitating the 3-aminobenzoxy compound as a hygroscopic solid. This solid was dried by dissolving it in 30 ml. of absolute ethanol, 10 ml. of benzene was added and the solution evaporated to dryness in vacuo. The residue was dissolved in 15 ml. of warm absolute ethanol and upon cooling 3.5 g. of 3(4'-aminobenzoxy) -4,4'diphenyl. -6- dimethylaminoheptane dihydrochloride crystallized. (M. P. 188-189).

Anal. calcd. for C2aHa4N2Oa2HCl: c, 66.79;

7.21; N. 5.57. Found: C, 67.12; H, 7.79; N, 6.05.

EXAIWP'LE 13 3(4' wcetoaminoben2oxw 4,4 diphenyZ-G-di methylaminoheptane 01H; CHz-CH:CH-CHr-CHCH1 0H1 N(CHa)a NBIO OCH:

1 g. of 3(4'-aminobenzoxy)-4,4-dipheny1-6-dimethylaminoheptane hydrochloride was heated to reflux temperature with 10 ml. of acetic anhydride for 1 hour. The solvents were removed in vacuo and the residue (1 g.) was dissolved in 5 ml. 0! absolute ethanol and 50 ml. of ether was added to yield upon cooling 0.75 g. of crystals of 3(4' -acetaminobenzoxy) -4,4-diphenyl-6-dimethylamino heptane hydrochloride hydrate, (M. P. 178-180" wherein Q is a basic radicaisel'ected from the REFERENCES CITED group consisting 01' dimethylamino and mor- T e f 110 ef Ce a of re rd! the pholino radicals; and hydrohalide salts thereof. t 5 g i g eren re CO H 2. 3-hydroxy-4,4-diphenyl -6- dimethylamino heptane; 5 UNITED STATES PATENTS 3. 3-hydroxy-4A-diphenyl -6- morpholinohep Number Name Date tane. 2,368,073 Tryon Jan. 23, 1945 4. 3-hydroxy-4,4-dipheny1-6- dimethylamino 2,431,285 Suter et a1. Nov. 18, 1947 heptane hydrochloride. 2,477,842 Wenner Aug. 2, 1949 5. 3-hydroxy- 4A-d1pheny1 -6- morpholinohep l0 tane hydrobromlde.

ROBERT L. CLARK. 

1. THE COMPOUND OF THE GROUP CONSISTING OF ALCOHOLS HAVING THE FORMULA: 